2,3-dihydro-4(1H)-pyridone derivatives , method for production thereof and pharmaceutical composition comprising the same

ABSTRACT

A compound selected from those of formula (I):  
                 
wherein: 
         R 1  represents hydrogen, aryl(C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )acyl, linear or branched (C 1 -C 6 )alkoxycarbonyl, aryl(C 1 -C 6 )alkoxycarbonyl, or trifluoroacetyl,    R 2  represents hydrogen, linear or branched (C 1 -C 6 )alkyl,    X represents oxygen or NOR 3 ,    R 3  represents hydrogen, linear or branched (C 1 -C 6 )alkyl optionally substituted by one or more identical or different groups selected from hydroxy, amino and linear or branched (C 1 -C 6 )alkoxy, Ar represents aryl or heteroaryl, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same which are useful in the treatment of cognitive disorders and which possess antalgic properties.

The present invention relates to new 2,3-dihydro-4(1H)-pyridonecompounds, to a process for their preparation, to pharmaceuticalcompositions containing them and to their use as facilitators of memoryand cognition and as antalgic agents.

Ageing of the population due to increased life expectancy has broughtwith it a major increase in cognitive disorders associated with normalcerebral ageing and with pathological cerebral ageing occurring in thecourse of neurodegenerative diseases such as, for example, Alzheimer'sdisease.

The majority of substances used today in treating cognitive disordersassociated with ageing act by facilitating the central cholinergicsystems—either directly, as in the case of acetylcholinesteraseinhibitors (tacrine, donepezil) and cholinergic agonists (nefiracetam),or indirectly, as in the case of nootropic agents (piracetam,pramiracetam) and cerebral vasodilators (vinpocetine).

Besides their cognitive properties, substances acting directly on thecentral cholinergic systems often have antalgic properties but also havehypothermic properties, which can be undesirable.

It has therefore been especially valuable to synthesise new compoundsthat are capable of opposing the cognitive disorders associated withageing and/or of improving cognitive processes and that can possessantalgic properties without having hypothermic activity.

4-Hydroxy- or 4-oxo-substituted 1-aza-2-alkyl-6-aryl-cycloalkanes and1-aza-2-alkyl-6-aryl-cycloalkenes have already been described in theliterature (J. Org. Chem. 1988, 53, 2426; Liebigs Ann. Chem. 1986, 11,1823; Synlett 1993, 9, 657; Tet. Lett. 1998, 39(3/4), 217), but nopharmacological activity has been described for those compounds. Patentapplication EP 0119087 describes 1-aza-2-alkyl-6-aryl-cycloalkanecompounds for use as antalgic agents.

More specifically, the present invention relates to compounds of formula(I):

wherein:

-   -   R₁ represents a hydrogen atom or an aryl(C₁-C₆)alkyl group in        which the alkyl moiety may be linear or branched, a linear or        branched (C₁-C₆)alkyl group, a linear or branched (C₁-C₆)acyl        group, a linear or branched (C₁-C₆)alkoxycarbonyl group, an        aryl(C₁-C₆)— alkoxycarbonyl group in which the alkoxy moiety may        be linear or branched, or a trifluoroacetyl group,    -   R₂ represents a linear or branched (C₁-C₆)alkyl group,    -   X represents an oxygen atom or NOR₃ wherein:        -   R₃ represents a hydrogen atom or a linear or branched            (C₁-C₆)alkyl group optionally substituted by one or more            identical or different groups selected from hydroxy, amino            (optionally substituted by one or two linear or branched            (C₁-C₆)-alkyl groups) and linear or branched (C₁-C₆)alkoxy,    -   Ar represents an aryl group or a heteroaryl group,        to their enantiomers, diastereoisomers and also to addition        salts thereof with a pharmaceutically acceptable acid, it being        understood that aryl is understood to be a phenyl, biphenyl,        naphthyl or tetrahydronaphthyl group, each of those groups being        optionally substituted by one or more identical or different        groups selected from halogen, linear or branched (C₁-C₆)alkyl,        hydroxy, linear or branched (C₁-C₆)alkoxy, trihalomethyl, nitro        and amino (optionally substituted by one or more linear or        branched (C₁-C₆)alkyl groups),        and a heteroaryl group is understood to be an aromatic, mono- or        bi-cyclic, 5- to 12-membered group containing one, two or three        hetero atoms selected from oxygen, nitrogen and sulphur, it        being understood that the heteroaryl group may be optionally        substituted by one or more identical or different groups        selected from halogen, linear or branched (C₁-C₆)alkyl, hydroxy,        linear or branched (C₁-C₆)alkoxy, trihalomethyl, nitro and amino        (optionally substituted by one or more linear or branched        (C₁-C₆)alkyl groups). Among the heteroaryl groups there may be        mentioned, without implying any limitation, thienyl, pyridyl,        furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and        isothiazolyl groups.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoricacid etc.

The preferred compounds of formula (I) are those wherein the group Xrepresents an oxygen atom.

The group R₁ to which preference is given in accordance with theinvention is a hydrogen atom or a linear or branched(C₁-C₆)alkoxycarbonyl group.

The term aryl used in respect of the group Ar as defined for formula (I)is preferably an optionally substituted phenyl group.

The term aryl used in respect of the group Ar as defined for formula (I)is more preferably a substituted phenyl group.

The term heteroaryl used in respect of the group Ar as defined forformula (I) is preferably an optionally substituted thienyl group or anoptionally substituted pyridyl group.

The invention relates more especially to the compounds of formula (I)which are:

-   -   tert-butyl 2-methyl-4-oxo-6-(2-thienyl)-3,4-dihydro-1        (2H)-pyridinecarboxylate    -   2-methyl-6-(2-thienyl)-2,3-dihydro-4(1H)-pyridone    -   tert-butyl 2-methyl-4-oxo-6-phenyl-3,4-dihydro-1        (2H)-pyridinecarboxylate    -   2-methyl-6-phenyl-2,3-dihydro-4(1H)-pyridone    -   tert-butyl 6-(3-chlorophenyl)-2-methyl-4-oxo-3,4-dihydro-1        (2H)-pyridine-carboxylate    -   6-(3-chlorophenyl)-2-methyl-2,3-dihydro-4(1H)-pyridone    -   tert-butyl        6-(6-chloro-3-pyridyl)-2-methyl-4-oxo-3,4-dihydro-1(2H)-pyridine-carboxylate    -   6-(6-chloro-3-pyridyl)-2-methyl-2,3-dihydro-4(1H)-pyridone.

The enantiomers, diastereoisomers and also the addition salts with apharmaceutically acceptable acid of the preferred compounds form anintegral part of the invention.

The invention relates also to a process for the preparation of compoundsof formula (I), characterised in that 4-methoxypyridine is reacted insuccession with phenyl chloroformate, with an organomagnesium compoundof formula (II):R₂MgBr  (II)

-   -   wherein R₂ is as defined for formula (I),    -   and with potassium tert-butoxide to yield a compound of formula        (III):        wherein R₂ is as defined hereinbefore,        which compound of formula (III) is reacted with butyllithium and        with iodine to yield an iodated compound of formula (IV):        wherein R₂ is as defined hereinbefore,        which compound of formula (IV) is reacted, in the presence of        tetrakis(triphenylphosphine)palladium(0), with a boronic acid of        formula (V):        ArB(OH)₂  (V)        wherein Ar is as defined for formula (I),        to yield a compound of formula (I/a), which is a particular case        of the compounds of formula (I):        wherein Ar and R₂ are as defined hereinbefore,        in which compound of formula (I/a) the amine function is        optionally deprotected according to conventional techniques of        organic synthesis to yield a compound of formula (I/b), which is        a particular case of the compounds of formula (I):        wherein R₂ and Ar are as defined hereinbefore,        which compound of formula (IIb) is optionally reacted with a        compound of the formula R′₁Y wherein R′₁ represents an        aryl(C₁-C₆)alkyl group in which the alkyl moiety may be linear        or branched, a linear or branched (C₁-C₆)alkyl group, a linear        or branched (C₁-C₆)acyl group, a linear or branched        (C₁-C₆)alkoxycarbonyl group, an aryl(C₁-C₆)— alkoxycarbonyl        group in which the alkoxy moiety may be linear or branched, or a        trifluoroacetyl group, and Y represents a leaving group, to        yield a compound of formula (I/c), which is a particular case of        the compounds of formula (I):        wherein Ar, R′₁ and R₂ are as defined hereinbefore,        the compounds of formulae (I/b) and (I/c) forming the compounds        of formula (I/d):        wherein Ar, R₁ and R₂ are as defined hereinbefore,        which compounds of formula (I/d) are optionally reacted with a        compound of the formula H₂N—OR₃ wherein R₃ is as defined for        formula (I), to yield a compound of formula (I/e), which is a        particular case of the compounds of formula (I):        wherein Ar, R₁, R₂ and R₃ are as defined hereinbefore,        the compounds of formulae (I/a) to (I/e) constituting the        totality of the compounds of formula (I), which are purified,        where necessary, according to conventional purification        techniques, are separated, if desired, into their isomers        according to conventional separation techniques and are        converted, if desired, into their addition salts with a        pharmaceutically acceptable acid.

In addition to the fact that the compounds of the present invention arenew, they exhibit properties facilitating cognitive processes andantalgic properties, rendering them of use in the treatment of cognitivedeficiencies associated with cerebral ageing and with neurodegenerativepathologies, such as Alzheimer's disease, Parkinson's disease, Pick'sdisease, Korsakoffs disease and frontal lobe and subcortical dementiasand in the treatment of pain.

The invention relates also to pharmaceutical compositions comprising asactive ingredient a compound of formula (I) together with one or moreappropriate, inert, non-toxic excipients. Among the pharmaceuticalcompositions according to the invention there may be mentioned moreespecially those that are suitable for oral, parenteral (intravenous orsubcutaneous) and nasal administration, tablets or dragees, sublingualtablets, gelatin capsules, lozenges, suppositories, creams, ointments,dermal gels, injectable preparations, drinkable suspensions etc.

The dosage used can be adapted according to the nature and the severityof the disorder, the administration route and the age and weight of thepatient. The dosage varies from 1 to to 500 mg per day in one or moreadministrations.

The following Examples illustrate the invention without limiting it inany way.

The starting materials used are products that are known or preparedaccording to known procedures.

The structures of the compounds described in the Examples weredetermined according to customary spectrophotometric techniques(infra-red, nuclear magnetic resonance, mass spectrometry).

PREPARATION 1: Tert-butyl 4-methoxy-2-methyl-1(2H)-pyridinecarboxylate

37.81 mmol of ethyl chloroformate are added to a solution, cooled to−25° C., of 37.43 mmol of 4-methoxypyridine in 100 ml of anhydroustetrahydrofuran under an argon atmosphere. After one hour's stirring at−25° C., 39.30 mmol of 3M methylmagnesium bromide are added dropwise.The reaction mixture is stirred for 30 minutes at −25° C. and then forone hour at ambient temperature. 100 ml of water are then added and theaqueous phase is then extracted twice with diethyl ether, dried overmagnesium sulphate, filtered and then concentrated under reducedpressure. The resulting oil is taken up in 100 ml of anhydroustetrahydrofuran, the solution is then cooled to −40° C., and then 0.15mmol of potassium tert-butoxide is added. The reaction mixture isstirred for 2 hours at −40° C. and for one hour at ambient temperature,and 100 ml of water are then added. The aqueous phase is extracted twicewith diethyl ether and then the organic phase is dried over magnesiumsulphate, filtered and concentrated under reduced pressure to give theexpected product.

PREPARATION 2: Tert-butyl6-iodo-2-methyl-4-oxo-3,4-dihydro-1(2H)-pyridine-carboxylate

40.48 mmol of n-butyllithium are added to a solution, at −60° C., of33.73 mmol of the compound of Preparation 1 in 100 ml of anhydroustetrahydrofuran under an argon atmosphere. Stirring is carried out for30 minutes at −60° C., and then 37.11 mmol of iodine are added. Afterstirring for 2 hours at −60° C. and then for one hour at ambienttemperature, 100 ml of a 1N aqueous hydrochloric acid solution are addedto the reaction mixture. The aqueous phase is extracted twice withdiethyl ether, and the organic phase is dried over magnesium sulphate,filtered and concentrated under reduced pressure. Purification bychromatography on silica gel (diethyl ether/petroleum ether: 4/6) yieldsthe expected product.

IR(KBr): v_(C═O)=1668, 1722 cm⁻¹.

EXAMPLE 1 Tert-butyl2-methyl-4-oxo-6-(2-thienyl)-3,4-dihydro-1(2H)-pyridinecarboxylate

There are introduced into a 100 ml flask 4.45 mmol of the compound ofPreparation 2, 0.22 mmol of tetrakis(triphenylphosphine)palladium(0) and20 ml of dimethoxyethane, then 5.34 mmol of thiophene-2-boronic acid and11.12 mmol of sodium hydrogen carbonate dissolved in 20 ml of water. Thereaction mixture is heated under reflux and with vigorous stirring forabout 5 hours. After cooling, the aqueous phase is extracted twice withchloroform and the organic phase is dried over calcium chloride,filtered and concentrated under reduced pressure. Purification bychromatography on silica gel (diethyl ether/petroleum ether: 4/6) yieldsthe expected product. Melting point: 90° C. IR (KBr): v_(C − O) = 1659,1718 cm⁻¹. Elemental microanalysis: % C % H % N calculated 61.41 6.534.77 found 61.34 6.71 4.86

EXAMPLE 2 2-Methyl-6-(2-thienyl)-2,3-dihydro-4(1H)-pyridone

2.73 mmol of the compound of Example 1, 10 ml of dichloromethane and27.27 mmol of trifluoroacetic acid are mixed. The reaction mixture isstirred at ambient temperature for 4 hours and then rendered alkaline bythe addition of a saturated aqueous potassium carbonate solution. Theaqueous phase is extracted twice with dichloromethane, and the organicphases are combined and then dried over calcium chloride, filtered andconcentrated under reduced pressure. Purification by chromatography onsilica gel (ethyl acetate) yields the expected product. Melting point:155° C. IR (KBr): v_(C = O) = 1605 cm⁻¹; v_(NH) = 3288 cm⁻¹. Elementalmicroanalysis: % C % H % N calculated 62.15 5.74 7.24 found 62.34 5.627.02

EXAMPLE 3 Tert-butyl2-methyl-4-oxo-6-phenyl-3,4-dihydro-1(2H)-pyridine-carboxylate

The expected product is obtained according to the process described inExample 1, using phenylboronic acid. Melting point: 99° C. IR (KBr):v_(C = O) = 1655, 1709 cm⁻¹. Elemental microanalysis: % C % H % Ncalculated 71.06 7.37 4.87 found 70.92 7.51 4.71

EXAMPLE 4 2-Methyl-6-phenyl-2,3-dihydro-4(1H)-pyridone

The expected product is obtained according to the process described inExample 2, starting from the compound of Example 3. Melting point: 161°C. IR (KBr): v_(C = O) = 1605 cm⁻¹; v_(NH) = 3268 cm⁻¹. Elementalmicroanalysis. % C % H % N calculated 76.98 7.00 7.48 found 77.21 7.067.22

EXAMPLE 5 Tert-butyl6-(3-chlorophenyl)-2-methyl-4-oxo-3,4-dihydro-1(2H)-pyridinecarboxylate

The expected product is obtained according to the process described inExample 1, using 3-chlorobenzeneboronic acid. Melting point: 101° C. IR(KBr): v_(C = O) = 1674, 1714 cm⁻¹. Elemental microanalysis: % C % H % Ncalculated 63.45 6.26 4.35 found 63.39 6.36 4.21

EXAMPLE 6 6-(3-Chlorophenyl)-2-methyl-2,3-dihydro-4(1H)-pyridone

The expected product is obtained according to the process described inExample 2, starting from the compound of Example 5. Melting point: 133°C. IR (KBr): v_(C = O) = 1605 cm⁻¹; v_(NH) = 3255 cm⁻¹. Elementalmicroanalysis: % C % H % N calculated 65.02 5.46 6.32 found 65.15 5.596.13

EXAMPLE 7 Tert-butyl2-methyl-4-oxo-6-(6-chloro-3-pyridyl)-3,4-dihydro-1(2H)-pyridinecarboxylate

The expected product is obtained according to the process described inExample 1, using 6-chloropyridine-3-boronic acid. Melting point: 115° C.IR (KBr): v_(C = O) = 1660, 1711 cm⁻¹. Elemental microanalysis: % C % H% N calculated 59.54 5.93 8.68 found 59.75 5.88 8.42

EXAMPLE 8 6-(6-Chloro-3-pyridyl)-2-methyl-2,3-dihydro-4(1H)-pyridone

The expected product is obtained according to the process described inExample 2, starting from the compound of Example 7. Melting point: 216°C. IR (KBr): v_(C = O) = 1613 cm⁻¹; v_(NH) = 3256 cm⁻¹. Elementalmicroanalysis: % C % H % N calculated 59.33 4.98 12.58 found 59.19 5.0812.39

Pharmacological Study of Compounds of the Invention

EXAMPLE 9 Body Temperature in the NMRI Mouse

The effects of the compounds of the present invention on bodytemperature were assessed in the adult male NMRI mouse. The rectaltemperature of the mice (18-20 g) was measured just beforepharmacological treatment (intraperitoneal route) with the compoundsbeing studied or their carriers (20 mg/kg). The mice were then placed inindividual cages (10×10×10 cm) and their rectal temperature was measuredevery 30 minutes during the 2 hours following treatment. The values werethe means (° C.) plus or minus the standard errors of the means, andinter-group comparisons were carried out by a single-factor varianceanalysis test followed, where appropriate, by a Dunnett test.

The results show that the compounds of the invention do not havehypothermic activity at doses up to 20 mg/kg.

EXAMPLE 10 Abdominal Contractions Induced by phenyl-p-benzoquinone (PBQ)in the NMRI Mouse

Intraperitoneal administration of an alcoholic solution of PBQ causesabdominal cramps in the mouse (SIEGMUND et al., Proc. Soc. Exp. Biol.,1957, 95, 729-731). The cramps are characterised by repeatedcontractions of the abdominal musculature, accompanied by extension ofthe hind limbs. Most analgesics antagonise these abdominal cramps(COLLIER et al., Brit. J. Pharmacol. Chem., 1968, 32, 295-310). At t=0min., the animals are weighed and the compound being studied isadministered by the IP route. A group of control animals is given thesolvent used for the compound. At t=30 min., an alcoholic solution ofPBQ (0.2%) is administered by the IP route in a volume of 0.25 ml/mouse.Immediately after administration of the PBQ, the animals are placed incylinders of plexiglass (L=19.5 cm; I.D.=5 cm). From t=35 min. to t=45min., the animals' reaction is observed and the experimenter notes thetotal number of abdominal cramps per animal. The table below shows thepercentage inhibition of the number of abdominal cramps measured in thecontrol animals, at the active dose of the compound studied.

The results obtained show that the compounds of the invention possessantalgic properties. Example Dose (mg/kg) Inhibition (%) 2 20 48% 3 2059% 6 20 48%

EXAMPLE 11 Social Recognition in the Wistar Rat

Initially described in 1982 by THOR and HOLLOWAY (J. Comp. Physiol.,1982, 96, 1000-1006), the social recognition test has subsequently beenproposed by various authors (DANTZER et al., Psychopharmacology, 1987,91, 363-368; PER10 et al., Psycho-pharmacology, 1989, 97, 262-268) forstudying the mnemocognitive effects of new compounds. The test is basedon the natural expression of the olfactory memory of the rat and itsnatural tendency to forget and allows evaluation of memorisation, byrecognition of a young congeneric animal, by an adult rat. A young rat(21 days), taken at random, is placed for 5 minutes in the cage housingan adult rat. With the aid of a video device, the experimenter observesthe social recognition behaviour of the adult rat and measures itsoverall duration. The young rat is then removed from the adult rat'scage and is placed in its own cage until the second introduction. Theadult rat is then given the compound under test (intraperitoneal route)and, after 2 hours, is again brought into the presence (5 minutes) ofthe young rat. The social recognition behaviour is then observed againand its duration measured. The table below shows the difference (T₂-T₁),expressed in seconds, between the “recognition” times of the 2encounters.

The results obtained show that the compounds of the invention verygreatly enhance memorisation, even at a low dose. Example Dose (mg/kg)T₂ − T₁ (s) ± sem 6 3 −21.4 ± 5.1 3 3 −25.3 ± 7.1 1 3 −17.4 ± 2.5 8 3−17.2 ± 4.6

EXAMPLE 12 Pharmaceutical Composition

Formulation for the preparation of 1000 tablets each comprising 10 mg ofactive ingredient: Compound of Example 1  10 g Hydroxypropylcellulose  2g Wheat starch  10 g Lactose 100 g Magnesium stearate  3 g Talc  3 g

1-9. (canceled)
 10. A compound of formula (I):

wherein: R₁ represents hydrogen, aryl(C₁-C₆)alkyl in which the alkylmoiety may be linear or branched, linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)acyl, linear or branched(C₁-C₆)alkoxycarbonyl, aryl(C₁-C₆)alkoxycarbonyl in which the alkoxymoiety may be linear or branched, or trifluoroacetyl, R₂ representslinear or branched (C₁-C₆)alkyl, X represents oxygen or NOR₃ wherein: R₃represents hydrogen, linear or branched (C₁-C₆)alkyl optionallysubstituted by one or more identical or different groups selected fromhydroxy, amino (optionally substituted by one or two linear or branched(C₁-C₆)alkyl groups) and linear or branched (C₁-C₆)alkoxy, Ar representsaryl or heteroaryl, it being understood that: aryl is a phenyl,biphenyl, naphthyl or tetrahydronaphthyl group, each of those groupsbeing optionally substituted by one or more identical or differentsubstituents selected from halogen, linear or branched (C₁-C₆)alkyl,hydroxy, linear or branched (C₁-C₆)alkoxy, trihalomethyl, nitro andamino (optionally substituted by one or more linear or branched(C₁-C₆)alkyl groups), and heteroaryl is an aromatic, monocyclic orbicyclic heterocycle that has from 5 to 12 ring atoms, and whichoptionally contains in the ring system, two or three hetero atomsselected from oxygen, nitrogen and sulphur, it being understood thatheteroaryl may be optionally substituted by one or more identical ordifferent substituents selected from halogen, linear or branched(C₁-C₆)alkyl, hydroxy, linear or branched (C₁-C₆)alkoxy, trihalomethyl,nitro and amino (optionally substituted by one or more linear orbranched (C₁-C₆)alkyl groups).
 11. A compound of claim 10, wherein Xrepresents oxygen.
 12. A compound of claim 10, wherein R₁ representshydrogen or linear or branched (C₁-C₆) alkoxycarbonyl.
 13. A compound ofclaim 10, wherein Ar represents an optionally substituted phenyl.
 14. Acompound of claim 10, wherein Ar represents a substituted phenyl.
 15. Acompound of claim 10, wherein Ar represents an optionally substitutedthienyl or an optionally substituted pyridyl.
 16. A compound of claim 10which is selected from: tert-butyl2-methyl-4-oxo-6-(2-thienyl)-3,4-dihydro-1 (2H)-pyridinecarboxylate,2-methyl-6-(2-thienyl)-2,3-dihydro-4(1H)-pyridone, tert-butyl2-methyl-4-oxo-6-phenyl-3,4-dihydro-1 (2H)-pyridinecarboxylate,2-methyl-6-phenyl-2,3-dihydro-4(1H)-pyridone, tert-butyl6-(3-chlorophenyl)-2-methyl-4-oxo-3,4-dihydro-1(2H)-pyridine-carboxylate,6-(3-chlorophenyl)-2-methyl-2,3-dihydro-4(1H)-pyridone, tert-butyl6-(6-chloro-3-pyridyl)-2-methyl-4-oxo-3,4-dihydro-1(2H)-pyridine-carboxylate and6-(6-chloro-3-pyridyl)-2-methyl-2,3-dihydro-4(1H)-pyridone.
 17. A methodfor treating a living animal body, including a human, afflicted with adisorder of memory and cognition comprising the step of administering tothe living animal body, including a human, an amount of a compound ofclaim 10, which is effective for alleviation of the disorder.
 18. Apharmaceutical composition useful in treating memory and cognitiondisorders comprising as active principle an effective amount of acompound of claim 10, together with are as more pharmaceuticallyacceptable excipients or vehicles.